Thursday, February 27, 2014

I've decided to try my hand at writing some short research highlights, like you'd find in Nature. These basically summarize new research to try and get people excited about it! These are quite jargony, so I apologize to my non-scientific audience, and I promise I'll be back with something new and exciting as soon as I submit my thesis.

The expression
of genes that are required for the proliferation and differentiation of cell
types are tightly controlled by a combination of transcription regulators and
epigenetic modifications such as chromatin remodeling. Haematopoeisis, the formation of blood cell
components, is guided by a specific type of chromatin regulating factors,
including Mll and Bmi1, that mediate the differentiation of haematopoetic stem
cells into mature blood cells. Huang and
colleagues used a large-scale in vivo
reverse genetic screen which targeted zebrafish gene orthologues to 425 human
chromatin regulating factors to help decode the epigenetic determinants of
blood cell differentiation.

The resulting
34 chromatin regulating factors that were identified included 15 that were
involved in the regulation of primitive haematopoeisis, and 29 that regulates
definitive haematopoeisis, including many chromatin factors that had not been
previously identified. This screen
identified a number of chromatin factor complexes with distinct functions with
respect to the regulation of haematopoeisis, including previously unidentified
members of the ISWI complex such as smarca1,
chrac1, and rsf1b. Future in vivo studies will help elucidate the
function of these chromatin factor complexes in the broader transcriptional
network of gene regulation in blood development.

Calcium (Ca2+)
maintains cellular function by playing a key role in a wide array of cellular
processes, including signal transduction, muscle contraction, and gene
expression. In animals, calcium is
sequestered in the mitochondria; however, the influx of large amounts of
calcium into the mitochondria through the calcium-mediated opening of the
permeatibility transition pore (PTP) can lead to cell death. The import of calcium into the mitochondria
is accomplished by the recently discovered mitochondrial calcium uniporter
(MCU). The study of MCU and the dynamics
of mitochondrial calcium levels may elucidate its role in cell death,
potentially leading to the development of MCU inhibitors with implications for
the management of a number of clinically important disease processes such as
ischaemia and neurodegeneration.

Using mice
lacking MCU (MCU-/-), Pan et al. were able to confirm the role of
MCU in mitochondrial calcium transport, as well as the effects of MCU on normal
mitochondrial metabolism. Despite a
normal phenotype, the skeletal muscle of MCU-/-
mice had a 75% decrease in calcium uptake levels, and displayed alterations in
the phosphorylation and activity of pyruvate dehydrogenase. As a result, MCU-/- mice had significantly impaired muscle strength
and endurance, and showed no evidence of calcium-induced PTP opening, though
this did not have a protective effect against cell death. These results illustrate one of the
mechanisms of calcium-mediated regulation of mitochondrial metabolism and
animal physiology.

Polymorphism is
a biological process in which differential gene expression leads to phenotypic
changes. This process is related to
biodiversity, genetic variation, and adaptation, yet the effect of these
polymorphisms on gene expression dynamics during development remains elusive. This study used the model species C. elegans at different developmental
stages, to examine the fluctuation in the timing, rate, and magnitude of gene
expression by expression quantitative trait loci (eQTL).

By using eQTL
mapping, the authors identified 900 cis-eQTL and 10 clusters of trans-eQTL able
to regulate gene expression in the worms over a 12-hour period. Genes significantly affected by cis-eQTL
contained higher variation in their untranslated regions (UTR), suggesting that
these regions are responsible for the alterations in gene expression. Cis-eQTL were found to be involved in
increasing or decreasing gene expression, while trans-eQTL clusters affected
gene expression via the alteration of gene expression timing. The approach used in this study could also be
applied to the genetic analysis of more complex systems, and may be useful for
characterizing the effect of genetic variation on physiology and disease
progression in humans.

Friday, February 21, 2014

The nature vs. nurture debate looks at whether our genes or
our relationship to our environment have a greater impact on our physical and
emotional development. While this is
normally a term used by psychologists studying human nature, there are also
implications at the molecular biology level, and is referred to as epigenetics.

Epigenetics is a really interesting concept because it kind
of supports Lamarck's ideas on evolution, which when I was going through my
early training as a biologist, was generally accepted to be laughably
wrong. Lamarckism is the idea that the diversity of life was caused by physical adaptation to an environment that was then passed on to offspring. It was comically compared to Darwin's theory of evolution using giraffes as an example. According to both Darwin and Lamarck, giraffes used to have short necks. Lamarckism explains the evolution of long necks being caused by giraffes needing to stretch their necks to reach the higher branches, which strengthened and stretched their necks, and their offspring inherited these traits. This is known as "soft inheritance", and always reminded me of a good Chuck Norris joke. Darwin would have explained giraffes' long necks as variations in DNA sequence that led to longer necks. We know DNA is inherited, so it was the more generally accepted concept. Of course, the evolution of giraffes' necks is far morecomplicated than both naturalists thought.

Anyway, the point is, epigenetics has been making a come-back. Epigenetics is used to describe changes that are made to the expression of genes (the copying, or transcription of genes into RNA and the subsequent translation of the RNA into proteins) that do not involve changes to the DNA sequence itself. This can be done by a whole host of really interesting mechanisms. One really interesting mechanism is chromatin remodeling. Chromatin is the combination of DNA and DNA-associated proteins that are found in cell nuclei. Here's a pretty good picture of what that looks like:

Chromatin remodeling works by rearranging those proteins so that some genes are more or less accessible, depending on their function. So basically, if you're exposed to a stressful environment, your chromatin might rearrange to make sure that genes that are involved in dealing with stress are more accessible to be copied into RNA and expressed as proteins, than genes that might not be so useful. Chromatin remodeling can be done through a whole host of processes, but the one I'll focus on is the addition of a methyl group to two of the four bases that makes up DNA. This is called DNA methylation.

A huge amount of human disorders are actually determined by DNA methylation and epigenetics as a whole, especially during fetal development. Epigenetics influences obesity, cancer development, susceptibility to cardiovascular disease and diabetes, and genetic disorders like Prader-Willi syndrome. And a lot of the epigenetic effects that humans encounter occur in utero. In particular, maternal diet during pregnancy can have a significant effect on which genes are expressed and which aren't. Maternal health and environment clearly has HUGE implications for public health (cough *listen up government* cough). For example, maternal folic acid intake is involved in the normal neural tube development in fetuses. In fact, it's so important, that most Canadian wheat and pasta is fortified with folic acid to avoid developmental defects.

I found two recent(ish) studies that looked at the epigenetic effect of diet. One study put pregnant mice on diets with varying protein levels and types, and then looked at the level of DNA methylation in the offspring and how this might affect physiology and metabolism. What the authors found is that low protein diets (a stressful environment) during pregnancy led to offspring with significantly disturbed gene expression in their livers. And it wasn't just genes specifically involved with protein metabolism that were affected, these were genome-wide alterations to gene expression in liver cells.

The second study looked at exposure to plastic-derived environmental compounds, like BPA, and their epigenetic effects on offspring. Female rats were exposed to different plastic-derived compounds, then bred. Offspring three generations later (referred to as F3 in science jargon) had higher rates of obesity, and uterine or testical disease. That means that the exposure of female rats to BPA affected their great-grandchildren! That's because exposure to BPA and other endocrine disrupters causes alterations in DNA methylation which is then inherited by offspring and passed on to subsequent generations.

Epigenetics is a cool way in which scientists are able to look at the ways in which our interactions with our environment, be it through diet or even exposure to compounds like BPA, can influence how our genes are expressed, and how our children are programmed to deal with a similar type of environment. The more we learn about epigenetics, hopefully the more we will learn about preventing non-communicable disease in humans. Epigenetics is inextricably linked to public health, and the best way to address the effects of obesity on public health is to focus on the upstream factors that influence it.

Disclaimer: this is in NO WAY meant to shame pregnant women or influence their behaviour, or promote nosy people telling pregnant women how to behave. My angle, besides science, is to promote taking action to provide better services and support to pregnant women.

Tuesday, February 11, 2014

I was at work yesterday doing some research on mental health and early childhood development, and I came across this awesome article about stress and aging. But I seriously geeked out because this article linked stress with cell aging and lifespan. I've always had a bit of an interest in telomere biology since a presentation on the subject in my 4th year microevolution class.

First, some terminology. Telomeres are the caps at the end of chromosomes. They are made of bits of DNA that don't encode any genes, and that protect the important parts of chromosomes from shortening.

DNA replication starts at the centre of the chromosome, rather than at the ends. The enzymes that replicate DNA (aka polymerases) can only encode in one direction. That means that one strand of DNA is copied in one straight shot (this is the leading strand). But since DNA is double stranded, that leaves the other strand uncopied, which would be a waste. To solve this problem, DNA polymerase copies the second strand (the lagging strand) in fragments.

Then DNA ligase comes in and seals the ends of the fragments, making a complete strand of DNA. The ligase can only work if it has two pieces of DNA fragments to seal together, so that means that the last fragment is left with the end missing. You can see how this would be a problem if the ends of our chromosomes contained important genes. But it's ok, because telomeres are there to protect our chromosomes, and they progressively get shorter. When telomeres run out, DNA replication stops and our cells age and die. Telomere erosion (how fast telomeres shorten) is based on DNA replication rate, exposure to compounds that cause DNA damage (both environmental and physiological), and telomerase activity. Research in telomere biology shows that the length of telomeres as well as the rate of telomere erosion can actually determine life spans and rate of aging across populations and species.

This article that I came across is a review article that looks at evidence of different types of stress at different points in our lives, and their effect on telomere length and telomere erosion. Our aging and susceptibility to disease can be influenced by exposure to stress as fetuses, infants, and children, as well as our mental health and lifestyle choices. Obviously everyone knows that chronic stress and unhealthy lifestyle can make us age faster, among all kinds of diseases, but this review gives us an idea as to the biological mechanisms for this link.

A lot of very important brain and nervous system developments happen in a fetus, and continues as infants develop. The researchers who wrote this paper have proposed that telomere length and telomerase activity is plastic during development and can change with different intrauterine and early life conditions. That means that if a pregnant woman experiences chronic stress, that may trigger some placental-fetal endocrine responses that could influence the rate of telomere erosion in offspring. The authors of the paper state that there isn't much information available on this process in humans, but there have been some studies in animals that have shown this link.

Stress and mental health in early childhood is becoming a greater public health concern because of its implications on physical, social, and mental development. Studies of children and adults reporting high levels of stress in childhood have been linked to shortened telomeres. One recent study that looked at cumulative stress in childhood (on-going family violence, bullying, maltreatment, and neglect) was associated with accelerated telomere erosion, and this effect was magnified with prolonged exposure to multiple stressors. But other studies were more inconclusive about the link between shorter telomeres and exposure to violence, so the link between the two may not be as straightforward.

The authors also looked at the effect of mental illness on telomere erosion. The idea is that mental illness causes stress responses in the body, which speeds up cellular aging. Remember that telomere erosion is dependent on compounds that can damage DNA, among other things. These compounds can include oxidants and stress hormones, which are heightened during stress. Chronic stress, like that experienced as a result of mental illness, may therefore be linked to telomere erosion. The studies that were reviewed in this paper looked at major depressive disorder, anxiety disorder, bipolar disorder, post-traumatic stress disorder, and schizophrenia. Generally, studies that look at telomere erosion and mental illness have been inconclusive, so it's hard to come to the conclusion that mental illness causes an increased shortening of telomeres. But one really interesting study looked at telomerase activity in individuals suffering from major depression disorder. They found that telomerase activity increased in these individuals who were not taking antidepressant medication, and that this activity decreased after subsequent use of antidepressants. They say that this increase in telomerase activity is likely to protect the cell against heightened stress response.

What's cool about telomere biology is that all of this is plastic, it is highly influenced by stress levels, lifestyle, and environment. So even if you were exposed to high stress as a child or you suffer from mental illness, there are other factors that can buffer the effects of these exposures on telomere erosion. No one experience determines how you age or your susceptibility to disease. A combination of experiences and exposure, lifestyle choices like healthy diet and exercise, etc. work together to influence your rate of cell replication and telomerase activity. This paper is especially interesting because it provides a biological basis for how stress causes cellular aging and disease.

Thursday, February 6, 2014

I haven't had much of
a chance to do much writing these days, besides the writing of my thesis. Despite my best intentions, I haven't had the
time to devote to really thinking about a topic enough to write something
meaningful and coherent. So, I'm gonna
cheat a little bit and write a post about the genetic modification of
plants. I want to make it clear here
though - this is a post about the science behind GMOs, NOT an argument about
Monsanto!

First, some history: the first transgenic
crop that was approved for consumption in the U.S. was the Flavr Savr tomato in
1994. This tomato was designed to delay ripening
after being picked to prolong its shelf-life for shipping. This was done by silencing the plant enzyme
polygalacturonase, which breaks down pectin in the cell wall, making the fruit
susceptible to fungal infection. Flavr
Savr tomatoes failed because of the business model of the company producing it.

Then came Bt corn, named for the integration of genes from the bacterial species Bacillus
thurigiensis, a soil-dwelling bacteria historically used as a pesticide. This bacteria is an awesome pesticide because
it produces a Cry protein, which paralyzes the digestive tract of insects and
they starve to death. Boom. Nature.
I know it sounds scary, but the important thing here is that the Cry
proteins bind to specific receptors in the insect gut - these receptors only
exist in Bt susceptible insects. HUMANS DO NOT HAVE THESE RECEPTORS. So if you
were to happen to consume some of this bacteria, it wouldn't do anything to
you. Likewise, corn that has been
modified to express Cry proteins is only harmful to the bugs eating it, not to
the humans eating it. Bt corn has been
accused of killing off monarch butterflies and bees, which has been found to beuntrue.

Ah yes, then came Golden rice. In my third year of university, I sat in my plant physiology class hearing about golden rice for the first time. I was in complete awe, and in that moment I decided I wanted to be involved in biotechnology in one way or another. Golden rice was modified to produce beta-carotene, a precursor of vitamin A. The idea was to prevent vit A deficiency, which is caused by malnutrition, and kills almost 700 000 children under the age of 5 annually. Naysayers argued and argued against golden rice, first saying there wasn't enough vitamin A being produced, so scientists went in and made new strains producing even more beta-carotene. Then came the arguments that the use of golden rice would create a slippery slope for more widespread GMO use. Because that's the real concern, forget the millions of people who are affected by vitamin deficiencies. Golden rice is still being argued over, but has generally been shown to have sufficient levels of beta-carotene, and that the levels are better than those in spinach, or in the supplements anti-GMO activists recommend instead of golden rice. Update (March 15th, 2014): the delay in making Golden Rice available has cost 1.4 million life years lost since 2002 in India alone. This accounts not only for those people who have died from vitamin A deficiency, but also productivity losses for people who have vitamin A deficiency-associated blindness and health disabilities. This accounts for approximately $199 million (USD) in economic losses, PER YEAR in India alone!

Now some of the more common arguments I hear against GMOs are along the lines of "how are the genes able to kill bugs but magically don't affect humans, I don't buy it." This is a legitimate argument someone made to my sister about GMOs. When she read it to me, I chuckled and replied "not magic, science!" See, the problem is that science literacy is very very low among the general public. But genes and proteins that are toxic to humans and animals are well known and easily identified in short-term lab studies. Making a genetically modified crop is not just making a guess and hoping for the best. No scientist is ever trying to get away with inserting compounds into plants that are going to kill humans. That's a really quick way to lose your funding and your lab.

There's also an ick factor about eating a plant that's been infused with bacterial genes, like Bt corn. But the thing is, there's bacteria all over all of your food at all times. You eat the food, and some of the bacterial genes get integrated into the genomes of your internal bacterial flora. That's just a natural process. It happens if you eat organic food too.

Clearly, given the length of this post, I could talk about this all day. Bear with me, I have one last point to make. Genetic modification has been going on for thousands of years. Plant breeding is genetic modification, and farmers have been using breeding to enhance traits in crops. The large size of an ear of corn is not something that was found naturally, it was created by breeding. Anti-GMO activists argue that breeding is safer than lab-based modifications. But they're not. See, when you make a modification in the lab, you modify ONE gene or pathway, and you have to perform test after test after test to prove its safety before you can even apply to do field trials, then more testing before your crop is approved for human consumption. But when farmers breed plants, all kinds of genes are being modified or affected, and there are no tests to prove safety or efficacy.

Of course, I completely understand the skepticism, it's your body and you deserve to know what you're putting into it. But I'm also a scientist who works in this stuff, so I understand the process, and all the thinking that goes into making GMOs. In fact, the more people understand the science behind the process, the more they come to agree about the benefits of GMOs.

About Me

Thanks for stopping by! This blog is dedicated to spreading science to the masses. I take exciting new research findings and interpret them in a way that's accessible to everyone. As often as possible I will try to use research findings that are published in open access journals. On occasion, I throw in some policy context, just so my policy skills don't get rusty. So peruse, learn something new, and enjoy!